Treatment of cutaneous neurofibromas with Mirdametinib

ABSTRACT

The present disclosure relates to methods for treating cutaneous neurofibromas (cNF) comprising administering to a patient in need thereof mirdametinib or a pharmaceutically acceptable salt thereof.

The present application claims the benefit of U.S. ProvisionalApplication No. 63/321,036, filed Mar. 17, 2022, and U.S. ProvisionalApplication No. 63/321,046, filed Mar. 17, 2022, each of which is herebyincorporated by reference.

FIELD OF THE INVENTION

Mirdametinib is an allosteric, small molecule targetingmitogen-activated protein kinase kinase (MEK).

Weiss describes a Phase II clinical trial of mirdametinib in subjectswith neurofibromatosis type 1 who have a plexiform neurofibroma (Weisset al., J. Clin. Oncol., 29, 797-806, 2021).

The present disclosure relates to methods for treating cutaneousneurofibromas (cNF) comprising administering to a patient in needthereof mirdametinib or a pharmaceutically acceptable salt thereof.

BACKGROUND

There are many clinical features associated with the neurogeneticcondition neurofibromatosis type 1 (NF1). However, the feature thataffects the majority of NF1 patients is the development of cutaneousneurofibromas (cNF). Neurofibromas are defined as histologically benign(WHO grade I) tumors composed of multiple cell types including Schwanncells, fibroblasts, immune cells (such as mast cells and macrophages),and other elements of nerve. Regardless of their location, allneurofibromas share certain histologic and cellular characteristics.

The most common and prominent location of neurofibromas is the skin(including the epidermis and dermis). Discrete lesions are oftenreferred to as dermal or cutaneous neurofibromas. cNF are benign and arenot known to have any malignant potential.

Although not life-threatening, cNF have a major effect upon quality oflife for most patients with NF1 due to their prevalence anddisfigurement. Furthermore, the number of cNF increases with age afteradolescence and throughout a patient's lifespan. Despite the highprevalence of cNF in people with NF1 and their documented influence onquality of life, current treatment is limited to surgical removal orphysical destruction.

There is a need for improved therapies for cutaneous neurofibromas.

BRIEF SUMMARY OF THE INVENTION

One aspect of the present invention is a method for treating cutaneousneurofibromas (cNF) in a human patient comprising administering to thepatient mirdametinib or a pharmaceutically acceptable salt thereof. Insome aspects, the patient in need thereof additionally hasneurofibromatosis 1 (“NF1”)

In some aspects, a therapeutically effective amount of mirdametinib, ora pharmaceutically acceptable salt thereof, is administered. In someaspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in an amount of about 1 mg/m² to about 10 mg/m²per day based on mirdametinib free base. In some aspects, themirdametinib, or a pharmaceutically acceptable salt thereof, isadministered in an amount of about 1 mg to about 10 mg per day based onmirdametinib free base.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in a single dosage form comprising about 0.1mg/m² to about 10 mg/m² based on mirdametinib free base. In someaspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in a single dosage form comprising about 0.1 mgto about 10 mg based on mirdametinib free base.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered once daily. In some aspects, the mirdametinib,or a pharmaceutically acceptable salt thereof, is administered twicedaily.

In one embodiment, the mirdametinib, or a pharmaceutically acceptablesalt thereof, is orally administered in an amount of about 1 mg/m² toabout 10 mg/m² per day based on mirdametinib free base.

In another embodiment, the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered in an amount of about 1mg to about 10 mg per day based on mirdametinib free base.

In yet another embodiment, the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered in an amount of about 2mg/m² per day based on mirdametinib free base.

In yet another embodiment, the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered in an amount of about 2mg per day based on mirdametinib free base.

In yet another embodiment, the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered in an amount of about 4mg per day based on mirdametinib free base.

In yet another embodiment, the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered in an amount of about 6mg per day based on mirdametinib free base.

In yet another embodiment, the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered in an amount of about 8mg per day based on mirdametinib free base.

In yet another embodiment, the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered twice daily in an amountof about 1 mg based on mirdametinib free base.

In yet another embodiment, the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered twice daily in an amountof about 2 mg based on mirdametinib free base.

In yet another embodiment, the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered twice daily in an amountof about 3 mg based on mirdametinib free base.

In yet another embodiment, the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered twice daily in an amountof about 4 mg based on mirdametinib free base.

In one embodiment of any of the methods described herein,

-   -   (a) for a patient having a body surface area no more than 0.69        m², the patient is initially orally administered 1 mg        mirdametinib twice daily,    -   (b) for a patient having a body surface area of 0.7 to 1.04 m²,        the patient is initially orally administered 2 mg mirdametinib        twice daily,    -   (c) for a patient having a body surface area of 1.05 to 1.49 m²,        the patient is initially orally administered 3 mg mirdametinib        twice daily, and    -   (d) for a patient having a body surface area of at least 1.5 m²,        the patient is initially orally administered 4 mg mirdametinib        twice daily.

In one embodiment, the maximum daily dose is 4 mg mirdametinib twicedaily.

In one embodiment, over each four week period, the mirdametinib isadministered for the first three weeks and discontinued for the last oneweek.

In another embodiment, the mirdametinib is administered daily withoutinterruption.

In one embodiment of any of the methods described herein, the doseadministered is reduced due to an adverse event, wherein the dose isreduced as follows:

-   -   (a) if the dose at the time of the event is 1 mg mirdametinib        twice daily, then the reduced daily dose is 1 mg orally        administered in the morning only;    -   (b) if the dose at the time of the event is 2 mg mirdametinib        twice daily, then the reduced daily dose is 2 mg orally        administered in the morning and 1 mg administered in the        afternoon or evening;    -   (c) if the dose at the time of the event is 3 mg mirdametinib        twice daily, then the reduced daily dose is 2 mg orally        administered twice daily; and    -   (d) if the dose at the time of the event is 4 mg mirdametinib        twice daily, then the reduced daily dose is 3 mg orally        administered twice daily. In one embodiment, the adverse event        resulting in the dose reduction is acneiform.

In one embodiment of any of the methods described herein, the methodfurther comprises prior to treatment (i) determining whether to selectmirdametinib as a treatment for the patient, and (ii) selectingmirdametinib as a treatment for the patient at least partially based onits objective response rate, where the objective response rate isdefined as at least a 20% decrease in tumor size using centrally readMRI volumetric analysis. In one embodiment, in step (i), mirdametinib isselected based on a response rate of at least 70%. In anotherembodiment, in step (i), mirdametinib is selected based on a responserate of at least 75%. In yet another embodiment, in step (i),mirdametinib is selected based on a response rate of at least 80%. Inyet another embodiment, in step (i), mirdametinib is selected based on aresponse rate of at least 85%. In yet another embodiment, in step (i),mirdametinib is selected based on a response rate of at least 90%. Inyet another embodiment, in step (i), mirdametinib is selected based on aresponse rate of at least 95%.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, exhibits high blood-brain-barrier penetration.

In one embodiment, the patient has the clinical diagnosis of NF1 usingthe NIH Consensus Conference and one or more of the following:

-   -   (a) six or more café-au-lait macules with a diameter>5 mm in        prepubertal and >15 mm in post-pubertal individuals;    -   (b) freckling in axilla or inguinal regions;    -   (c) optic glioma;    -   (d) two or more Lisch nodules;    -   (e) a distinctive bony lesion (dysplasia of the sphenoid bone or        dysplasia of thinning of long bone cortex); and    -   (f) a first degree relative with NF 1.

In another embodiment, the patient has a constitutional NF1 mutationdocumented in a Clinical Laboratory Improvement Amendments/College ofAmerican Pathologists certified lab.

In one embodiment of any of the methods described herein, the patient isa human. In one embodiment, the human is an adult. In anotherembodiment, the patient is 2 to 15 years of age.

In one embodiment of any of the methods described herein, the human hashad no prior exposure to MEK inhibitors.

In one embodiment of any of the methods described herein, themirdametinib, or a pharmaceutically acceptable salt thereof, isadministered orally. In some aspects, the mirdametinib, or apharmaceutically acceptable salt thereof, is dispersible in a potableliquid or orodispersible in a patient's saliva. In some aspects, themirdametinib, or a pharmaceutically acceptable salt thereof, isadministered orally as a solid dosage form. In some aspects, the soliddosage form is a tablet or capsule. In some aspects, the solid dosageform is a capsule.

In one embodiment of any of the methods described herein, themirdametinib, or a pharmaceutically acceptable salt thereof, isadministered as a monotherapy to cNF. In one embodiment of any of themethods described herein, the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is administered in combination with anotheractive ingredient and/or surgery to treat cNF.

DETAILED DESCRIPTION OF THE INVENTION Definitions

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures inorganic chemistry, medicinal chemistry, and pharmacology describedherein are those well-known and commonly employed in the art. Unlessdefined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this disclosure belongs.

In this specification and the appended claims, the singular forms “a,”“an” and “the” include plural referents unless the context clearlydictates otherwise. The terms “a” (or “an”), as well as the terms “oneor more,” and “at least one” can be used interchangeably herein. Incertain aspects, the term “a” or “an” means “single.” In other aspects,the term “a” or “an” includes “two or more” or “multiple.”

Furthermore, “and/or” where used herein is to be taken as specificdisclosure of each of the two specified features or components with orwithout the other. Thus, the term “and/or” as used in a phrase such as“A and/or B” herein is intended to include “A and B,” “A or B,” “A”(alone), and “B” (alone). Likewise, the term “and/or” as used in aphrase such as “A, B, and/or C” is intended to encompass each of thefollowing aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; Aand C; A and B; B and C; A (alone); B (alone); and C (alone).

The term “mirdametinib” refers to the single enantiomerN-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)benzamide(free base form). The teachings throughout the specification regardingmirdametinib equally apply to pharmaceutically acceptable salts ofmirdametinib.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat,or mouse. The terms “subject” and “patient” are used interchangeablyherein in reference, for example, to a mammalian subject, such as ahuman subject. The patient may be a pediatric patient.

The term “mg/m²” refers to the dose in milligrams per m² body surfacearea of the patient.

The term “pediatric” refers to a human subject under the age of 21 yearsat the time of treatment. The term “pediatric” can be further dividedinto various subpopulations including: neonates (from birth through thefirst 28 days of life); infants (29 days of age to less than two yearsof age); children (two years of age to less than 12 years of age); andadolescents (12 years of age through 21 years of age (up to, but notincluding, the twenty-second birthday)). See, e.g., Berhman R E,Kliegman R, Arvin A M, Nelson W E. Nelson Textbook of Pediatrics, 15thEd. Philadelphia: W.B. Saunders Company, 1996; Rudolph A M, et al.Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First L R. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins;1994. Younger pediatric patients in particular, such as neonates,infants and young children, can have difficulty swallowing wholecapsules or tablets.

The term “dispersible” as used herein refers to a composition (e.g., atablet, powder, granules, minitablets, or pellets) which disintegratesand/or dissolves when combined with water or another potable liquid(e.g., a non-water beverage), or a subject's own saliva when placed inthe subject's mouth, with or without the addition of agitation ortemperature modification. In some aspects, the dispersible compositiondisintegrates or dissolves within 10 minutes, 9 minutes, 8 minutes, 7minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1minute after being combined with water or another potable liquid. Suchdisintegration or dissolution need not be complete. For example, adispersible tablet may dissolve almost entirely, but some undissolvedparticulate matter may remain. Dispersible formulations of mirdametinibsuitable for the methods described herein include those described inU.S. Pat. No. 11,571,402, which is hereby incorporated by reference.

The term “orodispersible” refers to a composition which is capable ofdissolving or disintegrating in a subject's mouth (i.e., dissolving ordisintegrating in a subject's saliva) if administered orally, without arequirement of first dissolving or disintegrating in a separatecontainer.

As used herein, the terms “treat,” “treated,” and “treating” mean boththerapeutic treatment and prophylactic or preventative measures whereinthe object is to prevent or slow down (lessen) an undesiredphysiological condition, disorder, or disease, or obtain beneficial ordesired clinical results. Thus, those in need of treatment include thosealready diagnosed with or suspected of having the disorder. Beneficialor desired clinical results include, but are not limited to, alleviationof symptoms; diminishment of the extent of a condition, disorder, ordisease; stabilized (i.e., not worsening) state of condition, disorder,or disease; delay in onset or slowing of condition, disorder, or diseaseprogression; amelioration of the condition, disorder, or disease stateor remission (whether partial or total), whether detectable orundetectable; an amelioration of at least one measurable physicalparameter, not necessarily discernible by the patient; or enhancement orimprovement of condition, disorder, or disease. Treatment includeseliciting a clinically significant response without excessive levels ofside effects. Treatment also includes prolonging survival as compared toexpected survival if not receiving treatment. The term “therapeuticallyeffective amount” is meant to include the amount of a compound that,when administered, is sufficient to prevent development of, or alleviateto some extent, one or more of the symptoms of a disorder, disease, orcondition being treated. The term “therapeutically effective amount”also refers to the amount of a compound that is sufficient to elicit thebiological or medical response of a cell, tissue, system, animal, orhuman, which is being sought by a researcher, veterinarian, medicaldoctor, or clinician.

In certain aspects, a subject is successfully “treated” for a tumor,according to the methods described herein if the patient shows one ormore of the following: a reduction in the size of the tumor; relief ofone or more symptoms associated with the specific tumor; a reduction inthe volume of the tumor; improvement in quality of life; increasedprogression-free survival (PFS), disease-free survival (DFS), overallsurvival (OS), metastasis-free survival (MFS), complete response (CR),minimal residual disease (MRD), partial response (PR), stable disease(SD), a decrease in progressive disease (PD), an increased time toprogression (TTP), or any combination thereof. In some aspects,nationally or internationally accepted standards of treatment outcomesin a given tumor can be used to determine whether an effective amount ofmirdametinib meets any of these particular endpoints (e.g., CR, PFS,PR).

The terms “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refer to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, excipient, solvent, or encapsulatingmaterial. In one embodiment, each component is “pharmaceuticallyacceptable” in the sense of being compatible with the other ingredientsof a pharmaceutical formulation, and suitable for use in contact withthe tissue or organ of humans and animals without excessive toxicity,irritation, allergic response, immunogenicity, or other problems orcomplications, commensurate with a reasonable benefit/risk ratio. SeeRemington: The Science and Practice of Pharmacy, 21st Edition,Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook ofPharmaceutical Excipients, 5th Edition, Rowe et al., Eds., ThePharmaceutical Press and the American Pharmaceutical Association: 2005;and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds.,Gower Publishing Company: 2007; Pharmaceutical Preformulation andFormulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004(incorporated herein by reference).

The term “pharmaceutically acceptable salts” refers to the relativelynon-toxic, inorganic and organic acid addition salts of Compound A orCompound B. These salts can be prepared in situ in the administrationvehicle or the dosage form manufacturing process, or by separatelyreacting a purified compound of the invention in its free base form witha suitable organic or inorganic acid, and isolating the salt thus formedduring subsequent purification. Representative salts include thehydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate,acetate, valerate, oleate, palmitate, stearate, laurate, benzoate,lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate,tartrate, napthylate, mesylate, glucoheptonate, lactobionate, andlaurylsulphonate salts. See, e.g., Berge et al. (1977) “PharmaceuticalSalts”, J. Pharm. Sci. 66:1-19.

The pharmaceutically acceptable salts of the subject compounds includethe conventional nontoxic salts or quaternary ammonium salts of thecompounds, e.g., from non-toxic organic or inorganic acids. For example,such conventional nontoxic salts include those derived from inorganicacids such as hydrochloride, hydrobromic, sulfuric, sulfamic,phosphoric, and nitric acid; and the salts prepared from organic acidssuch as acetic, propionic, succinic, glycolic, stearic, lactic, malic,tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicyclic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, and isothionic acid.

The terms “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term “about”or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

Unless the context requires otherwise, the terms “comprise,”“comprises,” and “comprising” are used on the basis and clearunderstanding that they are to be interpreted inclusively, rather thanexclusively, and that Applicant intends each of those words to be sointerpreted in construing this patent, including the claims below.

II. Methods of Treatment

Methods for treating a patient having cutaneous neurofibromas (“cNF”),comprising administering to a patient in need thereof mirdametinib or apharmaceutically acceptable salt thereof are provided herein. In someaspects, the patient in need thereof additionally has neurofibromatosis1 (“NF1”).

In some aspects, a therapeutically effective amount of mirdametinib, ora pharmaceutically acceptable salt thereof, is administered.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in an amount of about 1 mg/m² to about 10 mg/m²per day based on mirdametinib free base, about 1.5 mg/m² to about 9.5mg/m² per day based on mirdametinib free base, about 2 mg/m² to about 9mg/m² per day based on mirdametinib free base, about 2.5 mg/m² to about8.5 mg/m² per day based on mirdametinib free base, about 3 mg/m² toabout 8 mg/m² per day based on mirdametinib free base, about 3.5 mg/m²to about 7.5 mg/m² per day based on mirdametinib free base, about 4mg/m² to about 7 mg/m² per day based on mirdametinib free base, about4.5 mg/m² to about 6.5 mg/m² per day based on mirdametinib free base, orabout 5 mg/m² to about 6 mg/m² per day based on mirdametinib free base.In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in an amount of about 1 mg/m² per day based onmirdametinib free base, about 1.5 mg/m² per day based on mirdametinibfree base, about 2 mg/m² per day based on mirdametinib free base, about2.5 mg/m² per day based on mirdametinib free base, about 3 mg/m² per daybased on mirdametinib free base, about 3.5 mg/m² per day based onmirdametinib free base, about 4 mg/m² per day based on mirdametinib freebase, about 4.5 mg/m² per day based on mirdametinib free base, about 5mg/m² per day based on mirdametinib free base, about 5.5 mg/m² per daybased on mirdametinib free base, about 6 mg/m² per day based onmirdametinib free base, about 6.5 mg/m² per day based on mirdametinibfree base, about 7 mg/m² per day based on mirdametinib free base, about7.5 mg/m² per day based on mirdametinib free base, about 8 mg/m² per daybased on mirdametinib free base, about 8.5 mg/m² per day based onmirdametinib free base, about 9 mg/m² per day based on mirdametinib freebase, about 9.5 mg/m² per day based on mirdametinib free base, or about10 mg/m² per day based on mirdametinib free base.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in an amount of about 1 mg to about 10 mg perday based on mirdametinib free base, about 1.5 mg to about 9.5 mg perday based on mirdametinib free base, about 2 mg to about 9 mg per daybased on mirdametinib free base, about 2.5 mg to about 8.5 mg per daybased on mirdametinib free base, about 3 mg to about 8 mg per day basedon mirdametinib free base, about 3.5 mg to about 7.5 mg per day based onmirdametinib free base, about 4 mg to about 7 mg per day based onmirdametinib free base, about 4.5 mg to about 6.5 mg per day based onmirdametinib free base, or about 5 mg to about 6 mg per day based onmirdametinib free base. In some aspects, the mirdametinib, or apharmaceutically acceptable salt thereof, is administered in an amountof about 1 mg per day based on mirdametinib free base, about 1.5 mg perday based on mirdametinib free base, about 2 mg per day based onmirdametinib free base, about 2.5 mg per day based on mirdametinib freebase, about 3 mg per day based on mirdametinib free base, about 3.5 mgper day based on mirdametinib free base, about 4 mg per day based onmirdametinib free base, about 4.5 mg per day based on mirdametinib freebase, about 5 mg per day based on mirdametinib free base, about 5.5 mgper day based on mirdametinib free base, about 6 mg per day based onmirdametinib free base, about 6.5 mg per day based on mirdametinib freebase, about 7 mg per day based on mirdametinib free base, about 7.5 mgper day based on mirdametinib free base, about 8 mg per day based onmirdametinib free base, about 8.5 mg per day based on mirdametinib freebase, about 9 mg per day based on mirdametinib free base, about 9.5 mgper day based on mirdametinib free base, or about 10 mg per day based onmirdametinib free base.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in a single dosage form comprising about 0.1mg/m² to about 10 mg/m² based on mirdametinib free base, about 0.5 mg/m²to about 9.5 mg/m² based on mirdametinib free base, about 1 mg/m² toabout 9 mg/m² based on mirdametinib free base, about 1.5 mg/m² to about8.5 mg/m² based on mirdametinib free base, about 2 mg/m² to about 8mg/m² based on mirdametinib free base, about 2.5 mg/m² to about 7.5mg/m² based on mirdametinib free base, about 3 mg/m² to about 7 mg/m²based on mirdametinib free base, about 3.5 mg/m² to about 6.5 mg/m²based on mirdametinib free base, about 4 mg/m² to about 6 mg/m² based onmirdametinib free base, or about 4.5 mg/m² to about 5.5 mg/m² based onmirdametinib free base. In some aspects, the mirdametinib, or apharmaceutically acceptable salt thereof, is administered in a singledosage form comprising about 0.1 mg/m² based on mirdametinib free base,about 0.2 mg/m² based on mirdametinib free base, about 0.3 mg/m² basedon mirdametinib free base, about 0.4 mg/m² based on mirdametinib freebase, about 0.5 mg/m² based on mirdametinib free base, about 1 mg/m²based on mirdametinib free base, about 1.5 mg/m² based on mirdametinibfree base, about 2 mg/m² based on mirdametinib free base, about 2.5mg/m² based on mirdametinib free base, about 3 mg/m² based onmirdametinib free base, about 3.5 mg/m² based on mirdametinib free base,about 4 mg/m² based on mirdametinib free base, about 4.5 mg/m² based onmirdametinib free base, about 5 mg/m² based on mirdametinib free base,about 5.5 mg/m² based on mirdametinib free base, about 6 mg/m² based onmirdametinib free base, about 6.5 mg/m² based on mirdametinib free base,about 7 mg/m² based on mirdametinib free base, about 7.5 mg/m² based onmirdametinib free base, about 8 mg/m² based on mirdametinib free base,about 8.5 mg/m² based on mirdametinib free base, about 9 mg/m² based onmirdametinib free base, about 9.5 mg/m² based on mirdametinib free base,or about 10 mg/m² based on mirdametinib free base.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in a single dosage form comprising about 0.1 mgto about 10 mg based on mirdametinib free base, about 0.5 mg to about9.5 mg based on mirdametinib free base, about 1 mg to about 9 mg basedon mirdametinib free base, about 1.5 mg to about 8.5 mg based onmirdametinib free base, about 2 mg to about 8 mg based on mirdametinibfree base, about 2.5 mg to about 7.5 mg based on mirdametinib free base,about 3 mg to about 7 mg based on mirdametinib free base, about 3.5 mgto about 6.5 mg based on mirdametinib free base, about 4 mg to about 6mg based on mirdametinib free base, or about 4.5 mg to about 5.5 mgbased on mirdametinib free base. In some aspects, the mirdametinib, or apharmaceutically acceptable salt thereof, is administered in a singledosage form comprising about 0.1 mg based on mirdametinib free base,about 0.2 mg based on mirdametinib free base, about 0.3 mg based onmirdametinib free base, about 0.4 mg based on mirdametinib free base,about 0.5 mg based on mirdametinib free base, about 1 mg based onmirdametinib free base, about 1.5 mg based on mirdametinib free base,about 2 mg based on mirdametinib free base, about 2.5 mg based onmirdametinib free base, about 3 mg based on mirdametinib free base,about 3.5 mg based on mirdametinib free base, about 4 mg based onmirdametinib free base, about 4.5 mg based on mirdametinib free base,about 5 mg based on mirdametinib free base, about 5.5 mg based onmirdametinib free base, about 6 mg based on mirdametinib free base,about 6.5 mg based on mirdametinib free base, about 7 mg based onmirdametinib free base, about 7.5 mg based on mirdametinib free base,about 8 mg based on mirdametinib free base, about 8.5 mg based onmirdametinib free base, about 9 mg based on mirdametinib free base,about 9.5 mg based on mirdametinib free base, or about 10 mg based onmirdametinib free base.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered one, two, three, or four times per day. In someaspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered once daily. In some aspects, the mirdametinib,or a pharmaceutically acceptable salt thereof, is administered twicedaily.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered twice daily in an amount of about 0.5 mg/m² toabout 10 mg/m² based on mirdametinib free base, about 1 mg/m² to about9.5 mg/m² based on mirdametinib free base, about 1.5 mg/m² to about 9mg/m² based on mirdametinib free base, about 2 mg/m² to about 8.5 mg/m²based on mirdametinib free base, about 2.5 mg/m² to about 8 mg/m² basedon mirdametinib free base, about 3 mg/m² to about 7.5 mg/m² based onmirdametinib free base, about 3.5 mg/m² to about 7 mg/m² based onmirdametinib free base, about 4 mg/m² to about 6.5 mg/m² based onmirdametinib free base, about 4.5 mg/m² to about 6 mg/m² based onmirdametinib free base, or about 5 mg/m² to about 6 mg/m² based onmirdametinib free base. In some aspects, the mirdametinib, or apharmaceutically acceptable salt thereof, is administered twice daily inan amount of about 0.5 mg/m² based on mirdametinib free base, about 1mg/m² based on mirdametinib free base, about 1.5 mg/m² based onmirdametinib free base, about 2 mg/m² based on mirdametinib free base,about 2.5 mg/m² based on mirdametinib free base, about 3 mg/m² based onmirdametinib free base, about 3.5 mg/m² based on mirdametinib free base,about 4 mg/m² based on mirdametinib free base, about 4.5 mg/m² based onmirdametinib free base, about 5 mg/m² based on mirdametinib free base,about 5.5 mg/m² based on mirdametinib free base, about 6 mg/m² based onmirdametinib free base, about 6.5 mg/m² based on mirdametinib free base,about 7 mg/m² based on mirdametinib free base, about 7.5 mg/m² based onmirdametinib free base, about 8 mg/m² based on mirdametinib free base,about 8.5 mg/m² based on mirdametinib free base, about 9 mg/m² based onmirdametinib free base, about 9.5 mg/m² based on mirdametinib free base,or about 10 mg/m² based on mirdametinib free base.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered twice daily in an amount of about 0.5 mg toabout 10 mg based on mirdametinib free base, about 1 mg to about 9.5 mgbased on mirdametinib free base, about 1.5 mg to about 9 mg based onmirdametinib free base, about 2 mg to about 8.5 mg based on mirdametinibfree base, about 2.5 mg to about 8 mg based on mirdametinib free base,about 3 mg to about 7.5 mg based on mirdametinib free base, about 3.5 mgto about 7 mg based on mirdametinib free base, about 4 mg to about 6.5mg based on mirdametinib free base, about 4.5 mg to about 6 mg based onmirdametinib free base, or about 5 mg to about 6 mg based onmirdametinib free base. In some aspects, the mirdametinib, or apharmaceutically acceptable salt thereof, is administered twice daily inan amount of about 0.5 mg based on mirdametinib free base, about 1 mgbased on mirdametinib free base, about 1.5 mg based on mirdametinib freebase, about 2 mg based on mirdametinib free base, about 2.5 mg based onmirdametinib free base, about 3 mg based on mirdametinib free base,about 3.5 mg based on mirdametinib free base, about 4 mg based onmirdametinib free base, about 4.5 mg based on mirdametinib free base,about 5 mg based on mirdametinib free base, about 5.5 mg based onmirdametinib free base, about 6 mg based on mirdametinib free base,about 6.5 mg based on mirdametinib free base, about 7 mg based onmirdametinib free base, about 7.5 mg based on mirdametinib free base,about 8 mg based on mirdametinib free base, about 8.5 mg based onmirdametinib free base, about 9 mg based on mirdametinib free base,about 9.5 mg based on mirdametinib free base, or about 10 mg based onmirdametinib free base.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in a total daily dose that does not exceedabout 10 mg/m² based on mirdametinib free base, about 9.5 mg/m² based onmirdametinib free base, about 9 mg/m² based on mirdametinib free base,about 8.5 mg/m² based on mirdametinib free base, about 8 mg/m² based onmirdametinib free base, about 7.5 mg/m² based on mirdametinib free base,about 7 mg/m² based on mirdametinib free base, about 6.5 mg/m² based onmirdametinib free base, about 6 mg/m² based on mirdametinib free base,about 5.5 mg/m² based on mirdametinib free base, about 5 mg/m² based onmirdametinib free base, about 4.5 mg/m² based on mirdametinib free base,about 4 mg/m² based on mirdametinib free base, about 3.5 mg/m² based onmirdametinib free base, about 3 mg/m² based on mirdametinib free base,about 2.5 mg/m² based on mirdametinib free base, about 2 mg/m² based onmirdametinib free base, or about 1.5 mg/m² based on mirdametinib freebase.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in a total daily dose that does not exceedabout 10 mg based on mirdametinib free base, about 9.5 mg based onmirdametinib free base, about 9 mg based on mirdametinib free base,about 8.5 mg based on mirdametinib free base, about 8 mg based onmirdametinib free base, about 7.5 mg based on mirdametinib free base,about 7 mg based on mirdametinib free base, about 6.5 mg based onmirdametinib free base, about 6 mg based on mirdametinib free base,about 5.5 mg based on mirdametinib free base, about 5 mg based onmirdametinib free base, about 4.5 mg based on mirdametinib free base,about 4 mg based on mirdametinib free base, about 3.5 mg based onmirdametinib free base, about 3 mg based on mirdametinib free base,about 2.5 mg based on mirdametinib free base, about 2 mg based onmirdametinib free base, or about 1.5 mg based on mirdametinib free base.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered as mirdametinib free base.

Methods for treating a patient having cutaneous neurofibromas (“cNF”),comprising administering to a patient in need thereof mirdametinib freebase are provided herein. In some aspects, patient additionally hasneurofibromatosis 1 (“NF1”).

In some aspects, a therapeutically effective amount of mirdametinib freebase is administered.

In some aspects, the mirdametinib free base is administered in an amountof about 1 mg/m² to about 10 mg/m² per day, about 1.5 mg/m² to about 9.5mg/m² per day, about 2 mg/m² to about 9 mg/m² per day, about 2.5 mg/m²to about 8.5 mg/m² per day, about 3 mg/m² to about 8 mg/m² per day,about 3.5 mg/m² to about 7.5 mg/m² per day, about 4 mg/m² to about 7mg/m² per day, about 4.5 mg/m² to about 6.5 mg/m² per day, or about 5mg/m² to about 6 mg/m² per day. In some aspects, the mirdametinib freebase is administered in an amount of about 1 mg/m² per day, about 1.5mg/m² per day, about 2 mg/m² per day, about 2.5 mg/m² per day, about 3mg/m² per day, about 3.5 mg/m² per day, about 4 mg/m² per day, about 4.5mg/m² per day, about 5 mg/m² per day, about 5.5 mg/m² per day, about 6mg/m² per day, about 6.5 mg/m² per day, about 7 mg/m² per day, about 7.5mg/m² per day, about 8 mg/m² per day, about 8.5 mg/m² per day, about 9mg/m² per day, about 9.5 mg/m² per day, or about 10 mg/m² per day.

In some aspects, the mirdametinib free base is administered in an amountof about 1 mg to about 10 mg per day, about 1.5 mg to about 9.5 mg perday, about 2 mg to about 9 mg per day, about 2.5 mg to about 8.5 mg perday, about 3 mg to about 8 mg per day, about 3.5 mg to about 7.5 mg perday, about 4 mg to about 7 mg per day, about 4.5 mg to about 6.5 mg perday, or about 5 mg to about 6 mg per day. In some aspects, themirdametinib free base is administered in an amount of about 1 mg perday, about 1.5 mg per day, about 2 mg per day, about 2.5 mg per day,about 3 mg per day, about 3.5 mg per day, about 4 mg per day, about 4.5mg per day, about 5 mg per day, about 5.5 mg per day, about 6 mg perday, about 6.5 mg per day, about 7 mg per day, about 7.5 mg per day,about 8 mg per day, about 8.5 mg per day, about 9 mg per day, about 9.5mg per day, or about 10 mg per day.

In some aspects, the mirdametinib free base is administered in a singledosage form comprising about 0.1 mg/m² to about 10 mg/m², about 0.5mg/m² to about 9.5 mg/m², about 1 mg/m² to about 9 mg/m², about 1.5mg/m² to about 8.5 mg/m², about 2 mg/m² to about 8 mg/m², about 2.5mg/m² to about 7.5 mg/m², about 3 mg/m² to about 7 mg/m², about 3.5mg/m² to about 6.5 mg/m², about 4 mg/m² to about 6 mg/m², or about 4.5mg/m² to about 5.5 mg/m^(2.) In some aspects, the mirdametinib free baseis administered in a single dosage form comprising about 0.1 mg/m²,about 0.2 mg/m², about 0.3 mg/m², about 0.4 mg/m², about 0.5 mg/m²,about 1 mg/m², about 1.5 mg/m², about 2 mg/m², about 2.5 mg/m², about 3mg/m², about 3.5 mg/m², about 4 mg/m², about 4.5 mg/m², about 5 mg/m²,about 5.5 mg/m², about 6 mg/m², about 6.5 mg/m², about 7 mg/m², about7.5 mg/m², about 8 mg/m², about 8.5 mg/m², about 9 mg/m², about 9.5mg/m², or about 10 mg/m^(2.)

In some aspects, the mirdametinib free base is administered in a singledosage form comprising about 0.1 mg to about 10 mg, about 0.5 mg toabout 9.5 mg, about 1 mg to about 9 mg, about 1.5 mg to about 8.5 mg,about 2 mg to about 8 mg, about 2.5 mg to about 7.5 mg, about 3 mg toabout 7 mg, about 3.5 mg to about 6.5 mg, about 4 mg to about 6 mg,about 4.5 mg to about 5.5 mg, or about 5 mg to about 6 mg. In someaspects, the mirdametinib free base is administered in a single dosageform comprising about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg,about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg,about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg.

In some aspects, the mirdametinib free base is administered one, two,three, or four times per day. In some aspects, the mirdametinib freebase is administered once daily. In some aspects, the mirdametinib freebase is administered twice daily.

In some aspects, the mirdametinib free base is administered twice dailyin an amount of about 0.5 mg/m² to about 10 mg/m², about 1 mg/m² toabout 9.5 mg/m², about 1.5 mg/m² to about 9 mg/m², about 2 mg/m² toabout 8.5 mg/m², about 2.5 mg/m² to about 8 mg/m², about 3 mg/m² toabout 7.5 mg/m², about 3.5 mg/m² to about 7 mg/m², about 4 mg/m² toabout 6.5 mg/m², about 4.5 mg/m² to about 6 mg/m², or about 5 mg/m² toabout 6 mg/m^(2.) In some aspects, the mirdametinib free base isadministered twice daily in an amount of about 0.5 mg/m², about 1 mg/m²,about 1.5 mg/m², about 2 mg/m², about 2.5 mg/m², about 3 mg/m², about3.5 mg/m², about 4 mg/m², about 4.5 mg/m², about 5 mg/m², about 5.5mg/m², about 6 mg/m², about 6.5 mg/m², about 7 mg/m², about 7.5 mg/m²,about 8 mg/m², about 8.5 mg/m², about 9 mg/m², about 9.5 mg/m², or about10 mg/m^(2.)

In some aspects, the mirdametinib free base is administered twice dailyin an amount of about 0.5 mg to about 10 mg, about 1 mg to about 9.5 mg,about 1.5 mg to about 9 mg, about 2 mg to about 8.5 mg, about 2.5 mg toabout 8 mg, about 3 mg to about 7.5 mg, about 3.5 mg to about 7 mg,about 4 mg to about 6.5 mg, about 4.5 mg to about 6 mg, or about 5 mg toabout 6 mg. In some aspects, the mirdametinib free base is administeredtwice daily in an amount of about 0.5 mg, about 1 mg, about 1.5 mg,about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg,about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, orabout 10 mg.

In some aspects, the mirdametinib free base is administered in a totaldaily dose that does not exceed about 10 mg/m², about 9.5 mg/m², about 9mg/m², about 8.5 mg/m², about 8 mg/m², about 7.5 mg/m², about 7 mg/m²,about 6.5 mg/m², about 6 mg/m², about 5.5 mg/m², about 5 mg/m², about4.5 mg/m², about 4 mg/m², about 3.5 mg/m², about 3 mg/m², about 2.5mg/m², about 2 mg/m², or about 1.5 mg/m^(2.)

In some aspects, the mirdametinib free base is administered in a totaldaily dose that does not exceed about 10.5 mg, 10 mg, about 9.5 mg,about 9 mg, about 8.5 mg, about 8 mg, about 7.5 mg, about 7 mg, about6.5 mg, about 6 mg, about 5.5 mg, about 5 mg, about 4.5 mg, about 4 mg,about 3.5 mg, about 3 mg, about 2.5 mg, about 2 mg, or about 1.5 mg.

In yet another embodiment, the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered in an amount of about 2mg/m² per day based on mirdametinib free base.

In yet another embodiment, the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered in an amount of about 2mg per day based on mirdametinib free base.

In yet another embodiment, the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered in an amount of about 4mg per day based on mirdametinib free base.

In yet another embodiment, the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered in an amount of about 6mg per day based on mirdametinib free base.

In yet another embodiment, the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered in an amount of about 8mg per day based on mirdametinib free base.

In yet another embodiment, the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered twice daily in an amountof about 1 mg based on mirdametinib free base.

In yet another embodiment, the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered twice daily in an amountof about 2 mg based on mirdametinib free base.

In yet another embodiment, the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered twice daily in an amountof about 3 mg based on mirdametinib free base.

In yet another embodiment, the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered twice daily in an amountof about 4 mg based on mirdametinib free base.

In one embodiment of any of the methods described herein,

-   -   (a) for a patient having a body surface area no more than 0.69        m², the patient is initially orally administered 1 mg        mirdametinib twice daily,    -   (b) for a patient having a body surface area of 0.7 to 1.04 m²,        the patient is initially orally administered 2 mg mirdametinib        twice daily,    -   (c) for a patient having a body surface area of 1.05 to 1.49 m²,        the patient is initially orally administered 3 mg mirdametinib        twice daily, and    -   (d) for a patient having a body surface area of at least 1.5 m²,        the patient is initially orally administered 4 mg mirdametinib        twice daily.

In one embodiment, the maximum daily dose is 4 mg mirdametinib twicedaily.

In one embodiment, over each four week period, the mirdametinib isadministered for the first three weeks and discontinued for the last oneweek.

In another embodiment, the mirdametinib is administered daily withoutinterruption.

In one embodiment of any of the methods described herein, the doseadministered is reduced due to an adverse event, wherein the dose isreduced as follows:

-   -   (a) if the dose at the time of the event is 1 mg mirdametinib        twice daily, then the reduced daily dose is 1 mg orally        administered in the morning only;    -   (b) if the dose at the time of the event is 2 mg mirdametinib        twice daily, then the reduced daily dose is 2 mg orally        administered in the morning and 1 mg administered in the        afternoon or evening;    -   (c) if the dose at the time of the event is 3 mg mirdametinib        twice daily, then the reduced daily dose is 2 mg orally        administered twice daily; and    -   (d) if the dose at the time of the event is 4 mg mirdametinib        twice daily, then the reduced daily dose is 3 mg orally        administered twice daily. In one embodiment, the adverse event        resulting in the dose reduction is acneiform.

In one embodiment of any of the methods described herein, the methodfurther comprises prior to treatment (i) determining whether to selectmirdametinib as a treatment for the patient, and (ii) selectingmirdametinib as a treatment for the patient at least partially based onits objective response rate, where the objective response rate isdefined as at least a 20% decrease in tumor size using centrally readMRI volumetric analysis. In one embodiment, in step (i), mirdametinib isselected based on a response rate of at least 70%. In anotherembodiment, in step (i), mirdametinib is selected based on a responserate of at least 75%. In yet another embodiment, in step (i),mirdametinib is selected based on a response rate of at least 80%. Inyet another embodiment, in step (i), mirdametinib is selected based on aresponse rate of at least 85%. In yet another embodiment, in step (i),mirdametinib is selected based on a response rate of at least 90%. Inyet another embodiment, in step (i), mirdametinib is selected based on aresponse rate of at least 95%.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, exhibits high blood-brain-barrier penetration.

In one embodiment, the patient has the clinical diagnosis of NF1 usingthe NIH Consensus Conference and one or more of the following:

-   -   (a) six or more café-au-lait macules with a diameter>5 mm in        prepubertal and >15 mm in post-pubertal individuals;    -   (b) freckling in axilla or inguinal regions;    -   (c) optic glioma;    -   (d) two or more Lisch nodules;    -   (e) a distinctive bony lesion (dysplasia of the sphenoid bone or        dysplasia of thinning of long bone cortex); and    -   (f) a first degree relative with NF 1.

In another embodiment, the patient has a constitutional NF1 mutationdocumented in a Clinical Laboratory Improvement Amendments/College ofAmerican Pathologists certified lab.

In one embodiment of any of the methods described herein, the patient isa human. In one embodiment, the human is an adult. In anotherembodiment, the patient is 2 to 15 years of age. In some aspects, thehuman has an age of >2 and <18 years.

In some aspects, the human has had no prior exposure to MEK inhibitors.In some aspects, the human has not responded to prior treatment to oneor more MEK inhibitors.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered orally. In some aspects, the mirdametinib, or apharmaceutically acceptable salt thereof, is administered orally as asolid dosage form. In some aspects, the solid dosage form is a tablet orcapsule. In some aspects, the solid dosage form is a capsule. In someaspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is dispersible in a potable liquid or orodispersible in apatient's saliva.

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered as a monotherapy to treat the cutaneousneurofibromas (“cNF”).

In some aspects, the mirdametinib, or a pharmaceutically acceptable saltthereof, is administered in combination with another active ingredientand/or surgery to treat the cutaneous neurofibromas (“cNF”).

EXAMPLE Example 1: Open-label, Multicenter Dose Finding Study toEvaluate the Safety and Tolerability and Anti-tumor Activity ofMirdametinib Monotherapy in Adult Patients with Neurofibromatosis 1(NF1) and Cutaneous Neurofibromas (cNF)

A Phase ½a open-label, multicenter dose finding study to evaluate thesafety and tolerability and anti-tumor activity of mirdametinibmonotherapy in adult patients with neurofibromatosis 1 (NF1) andcutaneous neurofibromas (cNF).

Phase 1 Study Objectives: The primary study objective is to assess thesafety and tolerability of mirdametinib monotherapy in adult patientswith NF1 and cNF and determine the RP2D (recommended phase 2 dose). Thesecondary study objective is to evaluate the anti-tumor activity ofmirdametinib monotherapy in adult patients with NF1 and cNF. Theexploratory study objectives are to assess the on-treatment effect ofmirdametinib on target inhibition (pERK, markers of apoptosis,mitogenetic markers and measures of the extra-cellular matrix proteins)in cutaneous neurofibroma(s) in adult patients with cutaneousneurofibromas (cNF) and NF 1.

Phase 2A (POC) Study Objectives: The primary study objective is toassess the safety of mirdametinib monotherapy in adult patients with NF1and cNF. The secondary study objective is to assess the efficacy ofmirdametinib monotherapy in adult patients with NF1 and cNF. Theexploratory study objectives are (1) to assess the quality-of-lifeimpact of mirdametinib monotherapy in adult patients with NF1 and cNF;and (2) assess the on-treatment effect of mirdametinib on targetinhibition (pERK, markers of apoptosis, mitogenetic markers and measuresof the extra-cellular matrix proteins) in cutaneous neurofibroma(s) inadult patients with cutaneous neurofibromas (cNF) and NF 1.

Study Design

The study will be conducted in two phases: 1) Phase 1, will test thesafety and tolerability of multiple dose cohorts of mirdametinib toidentify up to two doses for Phase 2a; 2) Phase 2a of the study willtest the efficacy and safety of up to two different doses inparticipants with NF1 and cNF.

In both Phases of the study, participation in the study will comprisethree periods: screening, treatment and post-study safety follow-up.

1. Screening Period (Phases 1 and 2a)

Participants will be screened for up to 28 days prior to first dose ofstudy treatment. Participant's disease diagnosis will be confirmed usingthe clinical and pathology reports available for the participant at thetime of screening initiation, written informed consent, clinical andlaboratory investigations to establish the eligibility of theparticipant for the trial will be completed.

Cardiac, ophthalmologic and laboratory examination (includingserum/urine pregnancy test), will be completed.

The two target areas will be chosen (7 cm×7 cm with a minimum of 6cutaneous neurofibromas of more than >0.5 cm); 2D photograph of thetarget areas will be taken to ensure tracking of the same lesions.

This is a routine care visit during which a usual clinical examinationis performed. Eligibility will be determined based on the screeningvisit.

The following patient-reported outcome measures will be completed:Skindex 26; Burden of Neurofibromatosis assessment tool; Visual AnalogicScale for pruritus;

For participants not enrolled, a brief reason will be entered.

Eligible participants will take their first dose of study treatmentfollowing all pre-dose assessments at Cycle 1 Day 1. All participantswill remain in the Treatment Phase of the study until diseaseprogression, they discontinue study treatment for any other reason, thestudy is stopped by the Sponsor for any reason, or the participant hascompleted the study through Cycle 12 for Phase 1 or Cycle 12 for Phase2a.

2. Treatment Period

Phase 1 Study: Participants would have completed screening prior to thefirst dose of study treatment (Mirdametinib). There will be 4 dosegroups each with a sample size of 6 participants.

-   -   1. Study treatment will be administered orally at a dose of 1 mg        BID, 2 mg BID, 3 mg BID or 4 mg BID for the 4 Dose Groups,        respectively.    -   2. Dosing will be on a 28-day Cycle (4-week course) with a        continuous dosing schedule. The Treatment Phase will last for up        to 12 Cycles followed by a 30-day Safety Follow-Up period (the        Safety Follow-Up visit is only required for participants who are        not continuing in the Phase 2a).    -   3. Study visits and participants evaluation will be as in the        schedule of activities.

Phase 2a Study: Participants previously enrolled in the selected RP2Dgroups of the Phase 1 will be enrolled in the Phase 2 Study.

-   -   1. Participants newly enrolling into the Phase 2 will be        screened for up to 28 days prior to the first dose of study        treatment (Mirdametinib). Participants meeting enrollment        criteria will be randomly assigned to either of the two active        treatment groups or to placebo.    -   2. Each group will have 12 participants for a total of up to 36        participants in the study. Study treatment will be administered        orally at a dose to be determined following the Phase 1 Study.        Dosing will be on a 28-day Cycle (4-week course) with a        continuous dosing schedule. The Treatment Phase will last for up        to 12 Cycles followed by a 30-day Safety Follow-Up period.    -   3. Assessment of endpoints and PRO will be performed, every 3        months (Pre-treatment baseline, M3, M6, M9, M12).    -   4. Subjects will complete a daily diary to record adverse events        and treatment adherence.

Safety Follow-Up Period (Phase 1 and Phase 2a)

The post-study follow-up (FU) visit will be performed at 30 days (±3days) after the last dose of study drug, except for subjects who died,withdrew consent and objected to further data collection, received newtreatment with a MEK-inhibitor or were lost to follow up.

The FU assessments can be done via a clinic visit (recommended) or via atelephone call (if subject cannot attend a clinic visit).

Phase 1 (Dose Finding)

In this phase, four different dose options of mirdametinib will betested in a maximum of 24 participants to identify the two doses to moveinto Phase 2. The two doses will be selected based on tolerability andefficacy signals. Each study arm will be enrolled and treatedconcurrently except for Dose Group 4. Dose Group 4 (4 mg BID continuousgroup) will not be initiated until the 3 mg BID dose has been deemedtolerable.

Cohort Management During Dose Finding

The dose groups will proceed in parallel. The actual number of dosegroups will be four; each group will have 6 participants for a total of24 participants in this phase of the study.

TABLE 1 Doses per dose group in Stage 1 Dose Group Dose 1 1 mg BID 2 2mg BID 3 3 mg BID 4 4 mg BID

Each dose group will start with a continuous dosing approach. If 2participants (33%) in a dose group develop a DLT (defined below) thenthat dose group will dose reduce to an intermittent (3 weeks on 1 weekoff) approach. If the DLTs do not resolve or if a further 33% (N=2) ofparticipants experience DLTs on the intermittent dosing approach, thenthat dose group will be terminated.

The first management decision will be made after at least 25% ofparticipants (N=6) complete C1 or experience a DLT.

Definition of dose-limiting toxicities (DLT)

DLT is defined as one or more of the following events occurring duringthe 28-day DLT period in Cycle 1, with the exclusion of toxicitiesclearly related to disease progression or intercurrent illness. Theseverity of DLTs will be graded according to the CTCAE v5.0.

Hematologic

-   -   Grade≤4 anemia.    -   Hematologic toxicity as defined by:        -   Grade 4 neutropenia lasting >5 days.        -   Grade 3 febrile neutropenia (defined as absolute neutrophil            count [ANC] <1000/mm³ with a single body temperature reading            of >38.3° C. (>101° F.) or a sustained temperature of            ≥38° C. (≥100.4° F.) for >1 hour.        -   Grade 4 thrombocytopenia or grade 3 thrombocytopenia with            clinically significant bleeding.

Non-hematologic

-   -   Grade≥3 ocular toxicities leading to reduced visual acuity        limiting activities of daily living (ADL), including but not        limited to glaucoma, retinal detachment, or retinal vascular        disorder.    -   Symptomatic decrease in left ventricular ejection fraction        (LVEF) or any other sign or symptom of congestive heart failure        (CHF).    -   Events meeting the criteria for Hy's law as follows (all 3        features):        -   Aspartate aminotransferase (AST) and/or alanine            aminotransferase (ALT)>3×upper limit of normal (ULN)        -   Concurrent elevation of total bilirubin>2×ULN without            initial evidence of cholestasis (elevated serum alkaline            phosphatase)        -   No alternative etiology can be identified    -   Grade≥3 significant neurologic toxicity (e.g., seizure,        hallucination, confusion or delirium)    -   Grade≥3 generalized muscle weakness.    -   Grade≥3 CK increase, if associated with the significant increase        in the skeletal muscle isoenzyme (CK-MM) confirmed by        electrophoretic fractionation and after ruling out the factors        unrelated to the study drug (e.g., physical exercise, trauma,        inflammatory comorbidity).    -   Grade≥3 skin rash that did not begin to resolve within 7 days of        initiating optimal medical and supportive care.    -   Grade≥3 non-hematologic toxicity not listed above (except        alopecia) that resolve to    -   Grade≤1 within 3 days of initiating optimal medical and        supportive therapy.

In addition, any clinically important or persistent toxicities that arenot included above may also be considered a DLT following review anddiscussion between the CMC and the sponsor.

The following toxicities may not be considered a DLT at theinvestigator's discretion after consultation with the Medical Monitor

-   -   Isolated Grade 3 or Grade 4 laboratory abnormalities not listed        above (e.g., lactose dehydrogenase elevation) that have no        clinical correlate and resolve to Grade≤1 within 3 days of        initiating optimal medical and supportive therapy.    -   Grade≥3 nausea, vomiting, diarrhea that resolves in ≤3 days, in        the absence of optimal medical therapy.    -   Grade≥3 fatigue that resolves in ≤5 days.    -   Grade≥3 asymptomatic elevation in lipase or amylase without        pancreatitis that lasts ≤3 days.

Phase 2a (Safety and Efficacy POC)

The objective of this phase will be to generate POC data on the safetyand anti-tumor efficacy of mirdametinib in treating cNF. In addition,PK/PD will be evaluated.

This Phase will start after 2 doses are selected from Phase 1 forfurther testing. Participants completing phase 1 on either of the tworecommended Phase 2 doses will continue in Phase 2 and the cohorts willbe expanded to 12 participants each.

Tracking cNF Lesions

To ensure the same lesions are measured over time during the study,‘Target Areas’ and ‘Target cNF’ lesions will be identified and marked atpre-treatment baseline.

Two ‘Target Areas’ (7 cm×7 cm with a minimum of 6 cutaneousneurofibromas ‘Target cNF’ lesions of >0.5 cm in their longest diameter)will be defined. 2D photography will be used to document the ‘TargetcNF’ lesions in relation to cutaneous landmarks in combination with apermanent map of the ‘Target Area’ created by marking the location ofeach cNF on a plastic sheet template placed over the participant'srelevant body region.

Measuring cNF Lesions

The study will use handheld 3D camera and digital calipers as measuringtools for the cNF lesions.

In screening, 3D photography or digital calipers (as locally preferred)will be used to evaluate the size of the cNF lesions for eligibility.

In Phase 1, both 3D photography and digital calipers will be used toassess tumor response.

In Phase 2a, the primary efficacy assessment will be based on the 3Dcamera and the digital calipers will be used as a secondary endpoint.

To minimize variability in measurements, the same technician/staff willbe used to acquire 3D images or caliper measurements throughout thetrial. A blinded central reviewer will be used for 3D image analysis.All photographs at each time point should be taken from the samedistance, using similar lighting and camera settings.

Study Population

Eligible patients will be adult patients (male and/or non-pregnantfemales), ≥18 years of age, confirmed with NF1, and who have a minimumof 12 measurable cutaneous neurofibromas (defined as non-pedunculated,surrounded by normal skin and not adjacent to another cNF lesion), eachmeasuring≥0.5 cm in the longest diameter and ≥0.5 cm in height, across 2‘Target Areas’ (defined as any 2 of the following body regions: head andneck; upper extremities; anterior chest wall; posterior chest wall,anterior abdominal wall; lower back; pelvic region/gluteal region; lowerextremities).

Eligibility Inclusion Inclusion Criteria

Participants must meet ALL the following criteria to be eligible for thestudy.

-   -   1. Participants must have EITHER the clinical diagnosis of NF1        using the

National Institute of Health (NIH) Consensus Conference criteria of atleast 1 other diagnostic criterion (Inclusion 2.1-2.6, see below) inaddition to the presence of plexiform neurofibroma (PN), OR have aconstitutional NF1 mutation documented in a Clinical LaboratoryImprovement Amendments/College of American Pathologists certified lab;additional criteria are as follows:

-   -   2.1. Six or more café-au-lait macules with a diameter>5 mm in        prepubertal and >15 mm in post-pubertal individuals,        respectively    -   2.2. Freckling in axilla or inguinal regions;    -   2.3. Optic glioma;    -   2.4. Two or more Lisch nodules;    -   2.5. A distinctive bony lesion (dysplasia of the sphenoid bone        or dysplasia of thinning of long bone cortex);    -   2.6. A first degree relative with NF1;    -   3. Participants must have a Karnofsky performance level of >80%.    -   4. Participant has adequate organ and bone marrow function as        defined by the following Screening laboratory values:        -   4.1. Absolute neutrophil count≥1500 cells/μL;        -   4.2. Platelets≥100×103/μL;        -   4.3. Hemoglobin≥9.5 g/dL;        -   4.4. Serum albumin≥2.8 g/dL;        -   4.5. Calculated creatinine clearance at Screening≥60 mL/min            (by Cockcroft-Gault formula) OR a normal serum creatinine.    -   5. Participant has the ability to swallow capsules whole if the        capsule dosage form is being utilized. This criterion does not        apply if participant is utilizing the dispersible tablet        (Pediatric Dosage formulation) dosage form of study treatment;    -   6. Participant is willing and able to comply with all aspects of        the protocol;

Contraception

-   -   7. Male or Female        -   Contraceptive use by men or women should be consistent with            local regulations regarding the methods of contraception for            those participating in clinical studies.        -   a. Male participants:            -   Male participants are eligible to participate if they                agree to the following during the treatment period and                for at least 90 days after the last dose of study                treatment:                -   Refrain from donating sperm            -   PLUS either:                -   Be abstinent from heterosexual intercourse as their                    preferred and usual lifestyle (abstinent on a long                    term and persistent basis) and agree to remain                    abstinent            -   OR                -   Must agree to use a male condom when having sexual                    intercourse with a woman of child bearing potential                    (WOCBP).        -   b. Female participants:            -   Female participants are eligible to participate if they                are not pregnant or breastfeeding, and at least one of                the following conditions applies:                -   Is not a woman of childbearing potential  OR                -   Is a WOCBP and using a contraceptive method that is                    highly effective (with a failure rate of <1% per                    year), preferably with low user dependency during                    the treatment period and for at least 30 days after                    the last dose of study treatment and agrees not to                    donate eggs (ova, oocytes) for the purpose of                    reproduction during the study and for a period of 90                    days after last dose of study treatment. The                    Investigator should evaluate the effectiveness of                    the contraceptive method in relationship to the                    first dose of study treatment.  A WOCBP must have a                    negative serum pregnancy test result at Screening                    and a negative urine pregnancy test result at the                    Baseline visit prior to the first dose of study                    treatment.                -   The Investigator is responsible for review of                    medical history, menstrual history, and recent                    sexual activity to decrease the risk for inclusion                    of a woman with an early undetected pregnancy;

Informed Consent/Assent

The Investigator, or a person designated by the Investigator, willobtain written informed consent from each study participant or theparticipant's legally acceptable representative, parent(s), or legalguardian and the participant's assent, when applicable, before anystudy-specific activity is performed. The Investigator will retain theoriginal copy of each participant's signed consent/assent document

Exclusion Criteria

Participants who meet ANY of the following criteria will not be eligiblefor the study.

Medical Conditions

Participant has a Screening alanine transaminase (ALT) valueof >2.0×upper limit of normal (ULN);

Participant has a Screening total bilirubin value of >1.5×ULN (isolatedbilirubin>1.5×ULN is acceptable if bilirubin is fractionated and directbilirubin<35%);

Participant has a history of malignancy associated hypercalcemia;

Participant has an active parathyroid disorder, hyperphosphatemia atScreening (serum phosphorus>1×ULN), or serum calcium (mg/dL)×serumphosphorus (mg/dL) product>70 at Screening;

Any clinically significant active or known history of liver disease, orknown hepatic or biliary abnormalities (with the exception of Gilbert'ssyndrome or asymptomatic gallstones);

-   -   a. Hepatitis serology and viral load will be tested at        Screening. Patients who are hepatitis B surface antigen (HBsAg)        positive or hepatitis C virus (HCV) antibody positive at        Screening must not be enrolled until further definite testing        with hepatitis B virus (HBV) deoxyribonucleic acid (DNA) titers        is <500 IU/mL or HCV ribonucleic acid (RNA) polymerase chain        reaction test is negative;

Lymphoma, leukemia, or any malignancy (including malignant glioma orMPNST) within the past 5 years except for basal cell or squamousepithelial carcinomas of the skin that have been resected with noevidence of metastatic disease for 3 years;

Breast cancer within the past 10 years;

Participants with evidence of an active optic glioma or other low-gradeglioma, requiring treatment with chemotherapy or radiation therapy.Participants not requiring treatment are eligible. Ophthalmologicalfindings secondary to long-standing optic pathway glioma (such as visualloss, optic nerve pallor or strabismus) or long-standing orbito-temporalPN (such as visual loss, strabismus) will NOT be considered asignificant abnormality for the purposes of the study;

Participant has abnormal QT interval corrected by Fridericia's formula(>450 msec for male participants, >470 msec for female participants,or >480 msec for participants with bundle branch block) (triplicate ECGreadings taken approximately 2 to 3 minutes apart and averaged) atScreening;

Participant has experienced any of the following within 6 months (24weeks) of signing informed consent/assent: clinically significantcardiac disease, myocardial infarction, severe/unstable angina,coronary/peripheral artery bypass graft, cerebrovascular accident,transient ischemic attack, or symptomatic pulmonary embolism;

Participant has recorded a LVEF<55% at Screening or within 3 years ofsigning informed consent/assent, OR has a history of congestive heartfailure;

Participant has a history of, or evidence of, retinal pathology onophthalmologic examination that is considered a risk factor for centralserous retinopathy, retinal vein occlusion (RVO), or neovascular maculardegeneration. Participants will be excluded from study participation ifthey have any of the following risk factors for RVO at Screening:

-   -   a. Intraocular pressure>21 mmHg;    -   b. Serum cholesterol>300 mg/dL;    -   c. Serum triglycerides>300 mg/dL;    -   d. Hyperglycemia (fasting blood glucose>125 mg/dL or random        blood glucose>200 mg/dL);    -   e. Age specific hypertension        -   i. Participants≤13 years of age with a blood pressure≤140/90            mm Hg        -   ii. Participants≤12 years of age with a blood            pressure≥95^(th) percentile for age+12 mmHg;

Participant has a history of glaucoma;

Participant has a history of a positive human immunodeficiency virus(HIV) antibody test;

Participant has a known malabsorption syndrome or preexistinggastrointestinal conditions that may impair absorption of mirdametinib(e.g., gastric bypass, lap band, or other gastric procedures). Deliveryof mirdametinib via nasogastric tube or gastrostomy tube is not allowed;

Prior/Concomitant Therapy

Participant previously received or is currently receiving therapy withmirdametinib;

Participant is receiving systemic or ocular glucocorticoid therapy (withthe exception of participants with endocrine deficiencies who areallowed to receive physiologic or stress doses of steroids, ifnecessary) within 14 days prior to first dose of study treatment;

Participant has received radiation therapy within the 6 months prior tosigning of informed consent/assent. Participants who have receivedradiation to the orbit at any time are excluded;

Prior/Concurrent Clinical Study Experience

Current enrollment or past participation in any other clinical study(excluding observational studies) within 28 days of signing of informedconsent/assent;

Other Exclusions

Sensitivity to the study treatment, or components thereof, or drug orother allergy that, in the opinion of the Investigator or MedicalMonitor, contraindicates participation in the study;

Participant with active bacterial, fungal, or viral infection includingbut not limited to the use of antibiotics, antifungals, or antiviralagents at the time of Screening;

Underlying medical conditions, laboratory abnormality, or alcohol ordrug abuse or dependence that, in the Investigator's opinion, will beunfavorable for the administration of study treatment or affect theexplanation of drug toxicity or adverse events; or insufficientcompliance during the study according to Investigator's judgement; or

Participant has experienced other severe acute or chronic medical orpsychiatric conditions, including recent (within 1 year of signinginformed consent/assent) or active suicidal ideation or behavior, or alaboratory abnormality that may increase the risk associated with studyparticipation or study treatment administration or may interfere withthe interpretation of study results and, in the judgment of theInvestigator, would make the participant inappropriate for entry intothis study.

All publications, patents, and patent applications mentioned in thisspecification are incorporated herein by reference in their entirety tothe same extent as if each individual publication, patent, or patentapplication was specifically and individually indicated to beincorporated by reference in its entirety. Where a term in the presentapplication is found to be defined differently in a documentincorporated herein by reference, the definition provided herein is toserve as the definition for the term.

While the invention has been described in connection with specificaspects thereof, it will be understood that invention is capable offurther modifications and this application is intended to cover anyvariations, uses, or adaptations following, in general, the principlesand including such departures from the present disclosure that comewithin known or customary practice within the art to which the inventionpertains and can be applied to the essential features hereinbefore setforth, and follows in the scope of the claimed.

1. A method for treating cutaneous neurofibromas (cNF) comprisingadministering to a human patient in need thereof, mirdametinib or apharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein the patient additionally has neurofibromatosis 1 (NF1).
 3. Themethod of claim 1, wherein the patient has the clinical diagnosis of NF1using the NIH Consensus Conference and one or more of the following: (a)six or more café-au-lait macules with a diameter>5 mm in prepubertaland >15 mm in post-pubertal individuals; (b) freckling in axilla oringuinal regions; (c) optic glioma; (d) two or more Lisch nodules; (e) adistinctive bony lesion (dysplasia of the sphenoid bone or dysplasia ofthinning of long bone cortex); and (f) a first degree relative with NF1.4. The method of claim 1, wherein the patient has a constitutional NF1mutation documented in a Clinical Laboratory ImprovementAmendments/College of American Pathologists certified lab.
 5. The methodof claim 1, wherein a therapeutically effective amount of mirdametinib,or a pharmaceutically acceptable salt thereof, is administered.
 6. Themethod of claim 1, wherein the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered in an amount of about 1mg/m² to about 10 mg/m² per day based on mirdametinib free base.
 7. Themethod of claim 1, wherein the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered in an amount of about 1mg to about 10 mg per day based on mirdametinib free base.
 8. The methodof claim 1, wherein the mirdametinib, or a pharmaceutically acceptablesalt thereof, is administered once daily.
 9. The method of claim 1,wherein the mirdametinib, or a pharmaceutically acceptable salt thereof,is administered twice daily.
 10. The method of claim 1, wherein themirdametinib, or a pharmaceutically acceptable salt thereof, is orallyadministered in an amount of about 2 mg/m² per day based on mirdametinibfree base.
 11. The method of claim 1, wherein the mirdametinib, or apharmaceutically acceptable salt thereof, is orally administered in anamount of about 2 mg per day based on mirdametinib free base.
 12. Themethod of claim 1, wherein the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered in an amount of about 4mg per day based on mirdametinib free base.
 13. The method of claim 1,wherein the mirdametinib, or a pharmaceutically acceptable salt thereof,is orally administered in an amount of about 6 mg per day based onmirdametinib free base.
 14. The method of claim 1, wherein themirdametinib, or a pharmaceutically acceptable salt thereof, is orallyadministered in an amount of about 8 mg per day based on mirdametinibfree base.
 15. The method of claim 1, wherein the mirdametinib, or apharmaceutically acceptable salt thereof, is orally administered twicedaily in an amount of about 1 mg based on mirdametinib free base. 16.The method of claim 1, wherein the mirdametinib, or a pharmaceuticallyacceptable salt thereof, is orally administered twice daily in an amountof about 2 mg based on mirdametinib free base.
 17. The method of claim1, wherein the mirdametinib, or a pharmaceutically acceptable saltthereof, is orally administered twice daily in an amount of about 3 mgbased on mirdametinib free base.
 18. The method of claim 1, wherein themirdametinib, or a pharmaceutically acceptable salt thereof, is orallyadministered twice daily in an amount of about 4 mg based onmirdametinib free base.
 19. The method of claim 1, wherein (a) for apatient having a body surface area no more than 0.69 m², the patient isinitially orally administered 1 mg mirdametinib twice daily, (b) for apatient having a body surface area of 0.7 to 1.04 m², the patient isinitially orally administered 2 mg mirdametinib twice daily, (c) for apatient having a body surface area of 1.05 to 1.49 m², the patient isinitially orally administered 3 mg mirdametinib twice daily, and (d) fora patient having a body surface area of at least 1.5 m², the patient isinitially orally administered 4 mg mirdametinib twice daily.
 20. Themethod of claim 1, wherein the maximum daily dose is 4 mg mirdametinibtwice daily.
 21. The method of claim 1, wherein over each four weekperiod, the mirdametinib is administered for the first three weeks anddiscontinued for the last one week.
 22. The method of claim 1, whereinthe dose administered is reduced due to an adverse event, wherein thedose is reduced as follows: (a) if the dose at the time of the event is1 mg mirdametinib twice daily, then the reduced daily dose is 1 mgorally administered in the morning only; (b) if the dose at the time ofthe event is 2 mg mirdametinib twice daily, then the reduced daily doseis 2 mg orally administered in the morning and 1 mg administered in theafternoon or evening; (c) if the dose at the time of the event is 3 mgmirdametinib twice daily, then the reduced daily dose is 2 mg orallyadministered twice daily; and (d) if the dose at the time of the eventis 4 mg mirdametinib twice daily, then the reduced daily dose is 3 mgorally administered twice daily.
 23. The method of claim 22, wherein theadverse event resulting in the dose reduction is acneiform.
 24. Themethod of claim 1, wherein the method further comprises prior totreatment (i) determining whether to select mirdametinib as a treatmentfor the patient, and (ii) selecting mirdametinib as a treatment for thepatient at least partially based on its objective response rate, wherethe objective response rate is defined as at least a 20% decrease intumor size using centrally read MM volumetric analysis.
 25. The methodof claim 25, wherein in step (i), mirdametinib is selected based on aresponse rate of at least 70%.
 26. The method of claim 1, wherein thepatient is 2 to 15 years of age.
 27. The method of claim 1, wherein thehuman is an adult.
 28. The method of claim 1, wherein the human patienthas no prior exposure to MEK inhibitors.
 29. The method of claim 1,wherein the mirdametinib, or a pharmaceutically acceptable salt thereof,is administered as a monotherapy.
 30. The method of claim 1, wherein themirdametinib, or a pharmaceutically acceptable salt thereof, isadministered in combination with another active ingredient and/orsurgery.